Androgens are the anabolic steroid hormones of animals, controlling muscle and skeletal mass, the maturation of the reproductive system, the development of secondary sexual characteristics and the maintenance of fertility in the male. In women, testosterone is converted to estrogen in most target tissues, but androgens themselves may play a role in normal female physiology, for example, in the brain. The chief androgen found in serum is testosterone, and this is the effective compound in tissues such as the testes and pituitary. In prostate and skin, testosterone is converted to dihydrotestosterone (DHT) by the action of 5α-reductase. DHT is a more potent androgen than testosterone because it binds more strongly to the androgen receptor.
Like all steroid hormones, androgens bind to a specific receptor inside the cells of target tissues, in this case the androgen receptor. This is a member of the nuclear receptor transcription factor family. Binding of androgen to the receptor activates it and causes it to bind to DNA binding sites adjacent to target genes. From there it interacts with coactivator proteins and basic transcription factors to regulate the expression of the gene. Thus, via its receptor, androgens cause changes in gene expression in cells. These changes ultimately have consequences on the metabolic output, differentiation or proliferation of the cell that are visible in the physiology of the target tissue.
Although modulators of androgen receptor function have been employed clinically for some time, both the steroidal (Basaria, S., Wahlstrom, J. T., Dobs, A. S., J. Clin Endocrino/Metab (2001), 86, pp5108-5117; Shahidi, N. T., Clin Therapeutics, (2001), 23, pp1355-1390), and non-steroidal (Newling, D. W., Br. J. Urol., 1996, 77 (6), pp 776-784) compounds have significant liabilities related to their pharmacological parameters, including gynecomastia, breast tenderness and hepatoxicity. In addition, drug-drug interactions have been observed in patients receiving anticoagulation therapy using coumarins. Finally, patients with aniline sensitivities could be compromised by the metabolites of non-steroidal antiandrogens.
Non-steroidal agonists and antagonists of the androgen receptor are useful in the treatment of a variety of disorders and diseases. More particularly, agonists of the androgen receptor could be employed in the treatment of prostate cancer, benign prostatic hyperplasia, hirsutism in women, alopecia, anorexia nervosa, breast cancer and acne. Antagonists of the androgen receptor could be employed in male contraception, male performance enhancement, as well as in the treatment of cancer, AIDS, cachexia, and other disorders.
Edwards, et.al., in WIPO publication W097/49709 and U.S. Pat. No. 6,017,924 disclose non-steroidal compounds that are high affinity, high selectivity modulators for androgen receptors.
Jones, et.al., in U.S. Pat. No. 5,696,130 disclose tricyclic, non-steroidal compounds that are high affinity, high selectivity modulators for androgen receptors.
Jones et. al., in WIPO publication WO95/11215 and U.S. Pat. No. 5,677,336 disclose non-steroid androgen receptor antagonists.
Friebe et. al., in WIPO publication WO95/02588 and U.S. Pat. No. 5,716,983 disclose coumarins and carbostyrils as PLA2 inhibitors.
Gaster et. al., in WIPO publication WO99/31086 disclose quinolinepiperazine and quinolinepiperidine derivatives and their use as combined 5-HT1A, 5HT1b and 5-HT1D receptor antagonists, useful in the treatment of CNS disorders.
More recently, Higuchi et al., in WIPO publication WO01/16139 disclose non-steroidal compounds that are modulators of androgen receptors.
Nonetheless, there exists a need for small molecule, non-steroidal antagonists of the androgen receptor. We now describe a novel series of (2-quinolonyl)-fused heterocyclic derivatives as androgen receptor modulators.